title: Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment.
abstract: OBJECTIVE
  Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.
  
  
  METHODS
  This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance.
  
  
  RESULTS
  DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma.
  
  
  CONCLUSIONS
  The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC, 27709, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Weller
authors.forename: Julie
authors.initials: J
authors.lastname: Borland
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Paul
authors.initials: P
authors.lastname: Savina
authors.forename: Brian
authors.initials: B
authors.lastname: Wynne
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Wajima
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Peppercorn
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
mesh_terms: D005260:Female; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D051437:Renal Insufficiency / Q000378:metabolism*; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir